Enzymes in lipid metabolism acquire and deliver hydrophobic substrates and products from within lipid bilayers. The structure at 2.55 Å of one isozyme of a constitutive enzyme in lipid A biosynthesis, LpxI from Caulobacter crescentus, has a novel fold. Two domains close around a completely sequestered substrate, UDP-2,3-diacylglucosamine, and open to release products either to the neighboring enzyme in a putative multienzyme complex or to the bilayer. Mutation analysis identifies Asp225 as key to Mg2+-catalyzed diphosphate hydrolysis. These structures provide snapshots of the enzymatic synthesis of a critical lipid A precursor.
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We dedicate this paper to the memory of coauthor Christian R.H. Raetz (1946–2011), our dear colleague and friend. We thank H.S. Chung, D.A. Six, Z. Guan, G. Laird, J.M. Holton, N.I. Nicely, J.E. Pak and J.W. Werner-Allen for helpful discussions. We thank H.J. Sage for analytical ultracentrifugation services. This research was supported by the US National Institutes of Health grants U54GM094625 (to R.M.S.), GM24485 (to R.M.S.), GM51310 (to C.R.H.R.) and GM069338 (to C.R.H.R.).